Disease relevance of FAP

• Because of its restricted normal tissue distribution and abundant expression in the stroma of over 90% of breast, colorectal, and lung carcinomas, FAP alpha is under clinical evaluation as a target for immunodetection and immunotherapy of epithelial cancers [1].
• The human fibroblast activation protein alpha (FAP alpha) is a M(r) 95,000 cell surface antigen selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas [1].
• Fibroblast activation protein alpha (FAPalpha) is highly expressed in epithelial cancers and has been implicated in extracellular matrix remodeling, tumor growth, and metastasis [2].
• The 170-kDa membrane-bound gelatinase, seprase, is a cell surface protease, the expression of which correlates with the invasive phenotype of human melanoma and carcinoma cells [3].
• Fibroblast activation protein (FAP) has been implicated in tumor growth and cirrhosis [4].

High impact information on FAP

• Reexpression of either wild-type or mutant DPPIV rescued expression of a second putative cell surface serine peptidase, fibroblast activation protein alpha, which can form a heterodimer with DPPIV [5].
• To specifically kill tumor-associated fibroblasts, we constructed an oral DNA vaccine targeting fibroblast activation protein (FAP), which is specifically overexpressed by fibroblasts in the tumor stroma [6].
• Three catalytic domains shared by DPPIV homologues in different species and by other serine proteases are conserved in FAP alpha [1].
• In the present study, we have isolated a full-length cDNA for FAP alpha through expression cloning in COS-1 cells [1].
• Circulating antiplasmin-cleaving enzyme (APCE) has a role in fibrinolysis and appears structurally similar to fibroblast activation protein (FAP), a cell-surface proteinase that promotes invasiveness of certain epithelial cancers [7].

Chemical compound and disease context of FAP

• Molecular cloning of seprase: a serine integral membrane protease from human melanoma [8].
• While investigating the above finding, we found that expression of CYP26A1, a major retinoic acid catabolic enzyme, was up-regulated in Apc(MIN) mouse adenomas, human FAP adenomas, human sporadic colon carcinomas, and in the intestine of apc(mcr) mutant zebrafish embryos [9].
• The NSAID (non-steroidal anti-inflammatory drug) sulindac is a potent inhibitor of intestinal carcinogenesis in the C57BL/6J-Apc(Min)/J mouse model and is used to treat humans with FAP (familial adenomatous polyposis) [10].
• We have recently shown that DPPIV can be downregulated from the cell surface of HT-29 colorectal carcinoma cells by adenosine, which is a metabolite that becomes concentrated in the extracellular fluid of hypoxic solid tumors [11].
• Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway [11].

Biological context of FAP

• The DPP10 gene is located on the long arm of chromosome 2 (2q12.3-2q14.2), close to the DPP4 (2q24.3) and FAP (2q23) genes [12].
• Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha [2].
• Seprase could be affinity-labeled by [3H]diisopropyl fluorophosphate, but the proteolytically inactive 97-kDa subunit could not, confirming the existence of a serine protease active site on the dimeric form [3].
• We also use the recent identification of the ADA binding protein as DPPIV to propose that the gene ADCP2 should be renamed DPP4 [13].
• FAP overexpression enhanced staurosporine streptomyces-stimulated apoptosis in both cell lines [14].

Anatomical context of FAP

• The putative serine protease activity of FAP alpha and its in vivo induction pattern may indicate a role for this molecule in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis [1].
• The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices [15].
• We have isolated seprase from cell membranes and shed vesicles of LOX human melanoma cells [3].
• Furthermore, expression of the seprase-DPPIV complex is restricted to migratory cells involved in wound closure in vitro and in connective tissue cells during closure of gingival wounds but not in differentiated tissue cells [16].
• Seprase is a homodimeric 170 kDa integral membrane gelatinase whose expression correlates with the invasiveness of the human melanoma cell line LOX [8].

Associations of FAP with chemical compounds

• Like DPPIV, the gelatinase activity of seprase was completely blocked by serine-protease inhibitors, including diisopropyl fluorophosphate [3].
• In this paper, we discuss the molecular interaction mechanism of diprotin A with hDPPIV based on the X-ray crystal structure [17].
• These substrate preferences allowed design of peptidyl-chloromethyl ketones that inhibited FAP, but not the related protease, dipeptidyl peptidase-4 [18].
• FAP required substrates with Pro at P(1) and Gly or d-amino acids at P(2) and preferred small, uncharged amino acids at P(3), but tolerated most amino acids at P(4), P(1)(') and P(2)(') [18].
• Dipeptide proline diphenyl phosphonates are potent, irreversible inhibitors of seprase (FAPalpha) [19].

Enzymatic interactions of FAP

• Known DPPIV dipeptides are cleaved by FAPalpha with an approximately 100-fold decrease in catalytic efficiency compared with DPPIV [2].

Regulatory relationships of FAP

• Here, we found the existence of a novel protease complex consisting of DPP4 and seprase in human endothelial cells that were activated to migrate and invade in the extracellular matrix in vitro [15].

Other interactions of FAP

• Thus, we used reverse transcription-polymerase chain reaction to generate a 2.4-kilobase cDNA from LOX mRNA with FAPalpha primers [3].
• Here we describe DPP8, a novel human postproline dipeptidyl aminopeptidase that is homologous to DPPIV and FAP [4].
• Synthesis and structure-activity relationship of N-alkyl Gly-boro-Pro inhibitors of DPP4, FAP, and DPP7 [20].
• FAP was colocalized with collagen fibers, fibronectin, and collagen type I in human liver [14].
• The functional interactions of DPIV and FAP with extracellular matrix confer roles for these proteins in cancer biology [21].

Analytical, diagnostic and therapeutic context of FAP

• Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers [1].
• Sequence analysis of three internal proteolytic fragments of the 97-kDa polypeptide revealed up to 87.5% identity to the 95-kDa fibroblast activation protein alpha (FAPalpha), the function of which is unknown [3].
• Northern-blot hybridization showed that the tissue expression of DPP8 mRNA is ubiquitous, similar to that of DPPIV [4].
• Immunoaffinity purification of FAP alpha followed by tryptic digestion, reversed-phase HPLC and microsequencing identified 3 unique FAP alpha peptides, with 2 showing sequence similarity (23/38 identical amino acids) to segments of CD26, a T-cell activation antigen [22].
• Progressive wild-type transthyretin deposition after liver transplantation preferentially occurs onto myocardium in FAP patients [23].

References